Establishing a platform for molecular analysis and drug innovation of auto-inflammatory disorders

• Project/Area Number: 26253062
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kyoto University
• Principal Investigator: Heike Toshio 京都大学, 医学研究科, 教授 (90190173)
• Co-Investigator(Kenkyū-buntansha): 八角 高裕 京都大学, 医学(系)研究科(研究院), 講師 (00511891) ; 小原 收 公益財団法人かずさDNA研究所, その他部局等, その他 (20370926) ; 河合 朋樹 京都大学, 医学(系)研究科(研究院), 助教 (20631568) ; 西小森 隆太 京都大学, 医学(系)研究科(研究院), 准教授 (70359800) ; 斎藤 潤 京都大学, 学内共同利用施設等, 准教授 (90535486)
• Research Collaborator: IZAWA Kazushi 京都大学, 大学院医学研究科発達小児科学, 助教 (90634931)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥41,340,000 (Direct Cost: ¥31,800,000、Indirect Cost: ¥9,540,000); Fiscal Year 2016: ¥12,740,000 (Direct Cost: ¥9,800,000、Indirect Cost: ¥2,940,000); Fiscal Year 2015: ¥13,520,000 (Direct Cost: ¥10,400,000、Indirect Cost: ¥3,120,000); Fiscal Year 2014: ¥15,080,000 (Direct Cost: ¥11,600,000、Indirect Cost: ¥3,480,000)
• Keywords: 自己炎症性疾患 / インフラマソーム / iPS細胞 / 病態解明 / モザイシズム / 単球・マクロファージ / 軟骨細胞 / 自己炎症疾患 / CAPS / 単球、マクロファージ

Outline of Final Research Achievements

We identified high-frequency somatic NLRC4 mosaicism as a cause of CAPS phenotype in a patient who lacks NLRP3 mutation through phenotype dissection using patient-derived iPS cells. For the analysis of pathophysiology of chondrohyperplasia in CAPS, we stablished isogenic iPSCs with wild-type and mutant NLRP3 derived from CAPS patients carrying NLRP3 somatic mosaicism, and found that mutant iPSCs produced larger chondrocyte masses through increased expression of the chondrocyte master regulator SOX9. We also investigated the pathophysiology of AGS (Aicardi-Goutieres Syndrome) by using IFIH1 mutant mice. These mice showed increased transcript levels of type I interferon response genes in various organs and encephalitis-like brain lesions, indicating that these mice are useful as an AGS disease model.

Research Products

• [Journal Article] Identification of a High-Frequency Somatic NLRC4 Mutation as a Cause of Autoinflammation by Pluripotent Cell-Based Phenotype Dissection. (2017)
  • Author(s): Kawasaki Y, Oda H, Ito J, Niwa A, Tanaka T, Hijikata A, Seki R, Nagahashi A, Osawa M, Asaka I, Watanabe A, Nishimata S, Shirai T, Kawashima H, Ohara O, Nakahata T, Nishikomori R, Heike T, Saito MK.
  • Journal Title: Arthritis Rheumatol. Volume: 69 Issue: 2 Pages: 447-459
  • DOI: 10.1002/art.39960
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Enhanced chondrogenesis of induced pluripotent stem cells from patients with neonatal-onset multisystem inflammatory disease occurs via the caspase 1-independent cAMP/protein kinase A/CREB pathway (2015)
  • Author(s): Yokoyama, K. Ikeya, M. Umeda, K. Oda, H. Nodomi, S. Nasu, A. Matsumoto, Y. Izawa, K. Horigome, K. Kusaka, T. Tanaka, T. Saito, M. K. Yasumi, T. Nishikomori, R. Ohara, O. Nakayama, N. Nakahata, T. Heike, T. Toguchida, J.
  • Journal Title: Arthritis Rheumatol Volume: 67 Issue: 1 Pages: 302-314
  • DOI: 10.1002/art.38912
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Derivation of mesenchymal stromal cells from pluripotent stem cells through a neural crest lineage using small molecule compounds with defined media. (2014)
  • Author(s): Fukuta M, Nakai Y, Kirino K, Nakagawa M, Sekiguchi K, Nagata S, Matsumoto Y, Yamamoto T, Umeda K, Heike T, Okumura N, Koizumi N, Sato T, Nakahata T, Saito M, Otsuka T, Kinoshita S, Ueno M, Ikeya M, Toguchida J.
  • Journal Title: PLOS ONE Volume: 9 Issue: 12 Pages: e112291-e112291
  • DOI: 10.1371/journal.pone.0112291
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes. (2014)
  • Author(s): Nakagawa K, Kawai T, Umebayashi H, Takei S, Kobayashi N, Yashiro M, Kubota T, Koike R, Akuta N, Shimoyama K, Iwata N, Saito MK, Ohara O, Kambe N, Yasumi T, Izawa K, Kawai T, Heike T, Yagüe J, Nishikomori R, Aróstegui JI et al.
  • Journal Title: Ann Rheum Dis. Volume: in press Issue: 3 Pages: 1-8
  • DOI: 10.1136/annrheumdis-2013-204361
  • Peer Reviewed / Open Access
• [Presentation] 己炎症性疾患診療の新展開～ベンチサイドとベッドサイドの連携 (2014)
  • Author(s): 平家俊男
  • Organizer: 第７１回日本小児科学会滋賀地方会
  • Place of Presentation: 滋賀医科大学
  • Year and Date: 2014-05-18
  • Invited
• [Presentation] 次世代シーケンサーを用いた“変異陰性TRAPS”における体細胞モザイクの検索 (2014)
  • Author(s): 19.中川権史、西小森隆太、河合朋樹、八角高裕、平家俊男
  • Organizer: 第117回日本小児科学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-04-11 – 2014-04-13
• [Presentation] 羅患者由来iPS細胞を用いたCINCA症候群における関節病態の解明 (2014)
  • Author(s): 13.横山宏司、西小森隆太、納富誠司郎、田中孝之、斉藤 潤、梅田雄嗣、池谷 真、中畑龍俊、戸口田淳也、平家俊男
  • Organizer: 第117回日本小児科学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-04-11 – 2014-04-13
• [Remarks] 京都大学医学部附属病院小児科
  • URL: http://www.kuhp.kyoto-u.ac.jp/~pediatrics/
• [Patent(Industrial Property Rights)] 軟骨過形成疾患の予防および治療剤ならびにそのスクリーニング方法 (2014)
  • Inventor(s): 戸口田 淳也/西小森 隆太/横山 宏司/池谷 真/平家 俊男
  • Industrial Property Rights Holder: 戸口田 淳也/西小森 隆太/横山 宏司/池谷 真/平家 俊男
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-227500
  • Filing Date: 2014-11-07